U.S. Pat. No. 5,280,040 and U.S. Pat. No. 5,464,862 discloses a class of 3,4-diarylchromans and their salts useful for reducing bone loss. U.S. Pat. No. 5,453,442 describes methods of lowering serum cholesterol and inhibiting smooth muscle cell proliferation in humans and inhibiting uterine fibroid disease and endometriosis in women by administering compounds of formula I as shown therein.
The preparation of 3,4-trans diarylchromanes is described in U.S. Pat. No. 3,822,287, the contents of which are incorporated herein by reference, and by Suprabhat Ray et al. in J.Med.Chem.19,276 (1976). The resolvation of (+/-)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-2-(pyrrolidin-1-yl)e thoxy!phenyl}chromane in its optical antipodes is described in U.S. Pat. No. 4,447,622 incorporated herein by reference. Example 1 describes the preparation of the minus enantiomer, shown by formula I: ##STR1## (In this specification the compound of formula I is referred to as levormeloxifene.)
In example 2 of U.S. Pat. No. 4,447,622 levormeloxifene is obtained as the free base and the hydrochloride salt.
However, the free base has a very poor solubility in water and the hydrochloride salt has some pharmaceutically undesirable properties. The hydrochloride salt is hygroscopic, it is quite heavy soluble in water and it forms a solid gel in aqueous suspension.
For commercial use it is important to have a physiologically acceptable salt with good stability, non-hygroscopicity, good bioavailability, good handling properties, and a reproducible crystalline form.